the Brain Matter of Us An Investigation on Memory

Consolidation

MIKE HUANG

Constructing

What is memory consolidation?

• Experiences Schemas – self construct, world views, social roles, beliefs, attitudes, knowledge, etc…

• Episodic Semantic – declarative/explicit• Context Dependent Context Independent• Hippocampal Dependent Hippocampal

Independent• MTL Neocortex• Short term - unstable Long term - stable• LTP Protein Synthesis

Overview of Presentation

• Systems consolidation: How do various brain regions interact with each other that forms/modifies our schemas?

• What is the nature of the episodic semantic memory interaction?

• Cellular consolidation: How does the incredibly intricately complex machinery in our cells work to consolidate memory?

Memory FormationExperience -> Ensemble of

bound HC(index) + NC neurons• Hippocampal dependency of

episodic memory

ConsolidationCombine related episodic

memories schemas• Schemas formed in neocortex

(context independent)ReconsolidationOlder memories = ↑traces = ↑retrievals = ↑integration of

experiences to schemas• New experiences old

memories recalled reorganization of old memories (context dependent)

Multiple Trace Theory: Transformation Hypothesis

A Computational Model

MTT Modeled to Account for Current Data

Hippocampal dependency of episodic memory

Neural dissociation of episodic/semantic

Recently retrieved memories = HC/context dependent

Evidence/Data: Hippocampal dependency of episodic memory

• Amnesia PatientsKC: MTL damage -> loss of all episodic memory/retention of semantic

memory

•Neural dissociation of episodic/semantic

Evidence/data: Recently retrieved memories = HC/context dependent

• Amnesia patients: – HM: hippocampus removal – 11yr temporally

graded amnesia

Evidence/data: Recently retrieved memories = HC/context dependent

• 25yr memory retrieval – hippocampus fMRI• Recent memory retrieval – hippocampus fMRI

• RESULT: Same activation!

Episodic -> Semantic interactions

• Material inconsistent w/ existing schema alter material to fit(1)

Neocortex

• Emotional memories enhances consolidation(2)

• Fear conditioning(4)

Amygdala

• Novelty(3)

• Emotional significance(3)VTA

Memory Formation in HC+NCEnthorhinal

Cortex Spatial

memory, context/event associations

CA1CA3Indexes of neocortical memory by LTP

Long Term Potentiation: Short-term Synaptic Plasticity

• Early LTP

Cellular Consolidation via Protein Synthesis: Long-Term Synaptic Plasticity

Evidence – Immediate Early Genes

• LTP’s molecular cascade induces gene expression– Ca2+ PKA cAMP CREB HAT gene expression – Ca2+ CaMKII gene expression

New techniques can block IEGs without controversial confounding side effects- antisense ODN - cellular compartment analysis of temporal activity by fluorescence in situ hybridization

Roles of IEGs• Activity induced RTFs: c-fos, c-jun, zif268

– transcribes more proteins: delayed effector genes

• Effector IEGs– Cellular growth

• BDNF• Narp

– Intracellular signaling• RheB• RGS-2• Homer 1a

– Synaptic modification• Arc• Homer 1a• Narp• Tissue plasminogen activator• BDNF

– Metabolism• COX-2

– Synaptic homeostasis• Arc• Homer 1a

Closeup Analysis of an Effector IEG - Arc

Activity Regulated Cytoskeleton-associated protein

• Shows up exactly in neural networks activated by behavior

• mRNA transport to and expression at activated synapses• Requisite for both late-LTP and long term memory

– EXPERIMENT: provide antisense ODN to block arc before training in water maze, compare with control.

– RESULT: blocked arc prevented learning– EXPERIMENT: arc KO mouse in spatial water maze task, cued and contextual fear conditioning,

conditioned taste aversion, object recognition, Failed learning

• Modification of synaptic function

Experience The birth of Arc

Plasticity PartnersαCaMKII Arc Expression

• Ca2+ αCaMKII Arc Expression• Expressed in striatum, hippocampus,

neocortex (1)

– In vitro αCaMKII in neuroblastoma cells -> Neurite outgrowth (2)

Functions of Arc

• Destabilizing the cytoskeleton through interactions with microtubule associate protein 2 (MAP2)– Co-pricipitate w/ actin and GluR4

• Homeostatic synaptic scaling through the endocytosis of AMPA receptors• Sleep, homeostatic synaptic scaling and memory consolidation

Arc regulation of synaptic networks

• catFISH - cellular compartment analysis of temporal activity by fluorescence in situ hybridization

– imaging of transcription activation with high temporal and cellular resolution

• Exploration of the same environment twice induced Arc in highly similar ensembles of neurons, whereas exploration of different environments induces Arc in distinct ensembles.

What about ALL the genes?